Shikonin Inhibites Migration and Invasion of Thyroid Cancer Cells by Downregulating DNMT1

Zhang, Yue; Sun, Bin; Huang, Zhi; Zhao, Dan; Zeng, Qingtao

doi:10.12659/msm.908381

Cited by 35 publications

(17 citation statements)

References 42 publications

(40 reference statements)

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“…Wang et al ( 38 ) reported that shikonin inhibited the proliferation and promoted apoptosis of breast cancer cells. The results of the present study demonstrated that shikonin could inhibit proliferation, migration and invasion, and increase the apoptosis of A549 cells in a dose-dependent manner, which were consistent with the findings of previous studies ( 36 – 38 ). However, the results of the present study showed a lower apoptosis rate, which is different to the results obtained in the aforementioned studies.…”

Section: Discussionsupporting

confidence: 93%

“…For example, a previous study reported that shikonin reduced the tumor diameter by 25% and increased the 1-year survival rate by 47.3% in patients with lung cancer ( 35 ). In addition, Zhang et al ( 36 ) demonstrated that shikonin inhibited the migration and invasion of thyroid cancer cells. Guo et al ( 37 ) also found that shikonin inhibited cell proliferation and induced apoptosis in glioma.…”

Section: Discussionmentioning

confidence: 99%

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Shikonin inhibits the Warburg effect, cell proliferation, invasion and migration by downregulating PFKFB2 expression in lung cancer

Sha

Liu

et al. 2021

Mol Med Rep

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Lung cancer is one of the most lethal diseases and therefore poses a significant threat to human health. The Warburg effect, which is the observation that cancer cells predominately produce energy through glycolysis, even under aerobic conditions, is a hallmark of cancer. 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB) is an important regulator of glycolysis. Shikonin is a Traditional Chinese herbal medicine, which has been reported to exert antitumor effects. The present study aimed to investigate the anticancer activity of shikonin in lung cancer. Cell Counting Kit-8 (CCK-8) and colony formation assays were used to analyze proliferation in A549 and H446 cells. Wound healing and Transwell assays were used to measure migration and invasion in A549 and H446 cells. Cell apoptosis was analyzed using flow cytometry. Lactate levels, glucose uptake and cellular ATP levels were measured using their corresponding commercial kits. Western blotting was performed to analyze the protein expression levels of key enzymes involved in aerobic glucose metabolism. Reverse transcription-quantitative PCR was used to analyze the mRNA expression levels of PFKFB2. The results of the present study revealed that PFKFB2 expression levels were significantly upregulated in NSCLC tissues. Shikonin treatment decreased the proliferation, migration, invasion, glucose uptake, lactate levels, ATP levels and PFKFB2 expression levels and increased apoptosis in lung cancer cells in a dose-dependent manner. The overexpression of PFKFB2 increased the proliferation, migration, glucose uptake, lactate levels and ATP levels in lung cancer cells, while the knockdown of PFKFB2 expression exerted the opposite effects. Moreover, there were no significant differences in lung cancer cell migration, apoptosis, glucose uptake, lactate levels and ATP levels between cells with knocked down PFKFB2 expression or treated with shikonin and the knockdown of PFKFB2 in cells treated with shikonin. In conclusion, the results of the present study revealed that shikonin inhibited the Warburg effect and exerted antitumor activity in lung cancer cells, which was associated with the downregulation of PFKFB2 expression.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Shikonin inhibits the Warburg effect, cell proliferation, invasion and migration by downregulating PFKFB2 expression in lung cancer

Sha

Liu

et al. 2021

Mol Med Rep

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“…The molecular mechanisms underlying the anti-cancer activity of Shikonin seemed to be complicated and may depend on the cellular context (Wang et al, 2019). So far, the reported cellular targets of Shikonin include the pyruvate kinase isoenzyme M2 (PKM2) (Chen et al, 2011;Lu et al, 2018;Tang et al, 2018b), the MAPK pathway (Mao et al, 2008;Zhao et al, 2015;Shan et al, 2017), HIF1a (Li et al, 2017;Han et al, 2018;Tang et al, 2018b), JNK (Zhai et al, 2017;Lin et al, 2018), PI3K/AKT (Zhang et al, 2015;Zhou et al, 2017;Ni et al, 2018;Tang et al, 2018b), STAT3 (Qiu et al, 2017;Tang et al, 2018a), p16INK4A and p73 (Jang et al, 2015), and PTEN (Nigorikawa et al, 2006;Chen et al, 2018;Zhang et al, 2018). These findings, at one hand, demonstrate that Shikonin can regulate various biological processes (Wang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Shikonin Inhibits Cancer Through P21 Upregulation and Apoptosis Induction

et al. 2020

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Shikonin is a natural naphthoquinone compound and has demonstrated potent anticancer activities; however, the underlying molecular mechanisms remained elusive. Here we report that Shikonin inhibited the growth of a wide range of human cancer cell lines, illustrating a broad anticancer effect. Mechanistically, we show that Shikonin arrested the cell cycle at the G2/M phase, inhibited the ERK-dependent cell growth signal, and induced cell death in both P53 wild type and mutant cancer cells, which collectively contributed to the growth inhibitory effect of Shikonin. A pan-apoptosis inhibitor largely suppressed Shikonin-induced cell death, suggesting an important role of apoptosis in this process. Intriguingly, Shikonin also activated autophagy and inhibition of autophagy by depleting critical autophagic genes further increased Shikonin-induced cell death, indicating a protective role of autophagy. In uncovering the molecular mechanisms underlying these effects of Shikonin, we found that Shikonin induced a robust upregulation of P21 independent of the P53 status, upregulated autophagy genes, as well as inhibited expression of genes required for cell growth. Using mouse tumor models, we confirmed the strong anticancer effect of Shikonin in vivo. Together, our data reveal a broad range of pharmacological functions of Shikonin, involving simultaneous growth inhibition, cell cycle arrest, autophagy activation and apoptosis induction through regulating expression of critical genes involved in these pathways. Our study may facilitate the development of Shikonin in cancer therapy as a single agent or in combination with other anticancer therapies.

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“…It has been demonstrated that DNMT1 is an essential methyltransferase for the maintenance of DNA methylation. Previous evidence has shown that DNMT1 is overexpressed in breast cancer [41], thyroid cancer cells [42], and pancreatic cancer [43]. Furthermore, high DNMT1 expression is signi cantly associated with a poor prognosis [44,45].…”

Section: Discussionmentioning

confidence: 98%

Uncovering of the Association Between m5C Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characteristics in Hepatocellular Carcinoma

Zhou

Chu

et al. 2021

Preprint

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Background: 5-Methylcytosine (m5C) plays essential roles in hepatocellular carcinoma (HCC), but the association between m5C regulation and immune cell infiltration in HCC has not yet been clarified.Methods: In this study, we analysed 371 patients with HCC from The Cancer Genome Atlas (TCGA) database, and the expression of 13 m5C regulators was investigated. Additionally, gene set variation analysis (GSVA), unsupervised clustering analysis, single-sample gene set enrichment analysis (ssGSEA), correlation analysis, and immunohistochemical (IHC) staining were performed.Results: Among the 371 patients, 41 had mutations in m5C regulators, the frequency of which was 11.26%. Then, we identified three m5C modification patterns that had obvious tumour microenvironment (TME) cell infiltration characteristics. Cluster-1 had an immune rejection phenotype; Cluster-2 had an immunoinflammatory phenotype; and Cluster-3 had an immune desert phenotype. In addition, we found that DNMT1 was highly expressed in tumour tissues compared with normal tissues in a tissue microarray (TMA) and that it was positively correlated with many TME-infiltrating immune cells. High expression of the m5C regulator DNMT1 was related to a poor prognosis in patients with HCC. Furthermore, we developed three Immu-clusters that were consistent with the immune characteristics of the m5C methylation modification patterns. We also discovered differences in the levels of immune cells and expression of chemokines and cytokines among the three Immu-clusters.Conclusions: Our work revealed the association between m5C modification and immune regulators in the TME. These findings also suggest that DNMT1 has great potential as a prognostic biomarker and therapeutic target for HCC.

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Shikonin Inhibites Migration and Invasion of Thyroid Cancer Cells by Downregulating DNMT1

Cited by 35 publications

References 42 publications

Shikonin inhibits the Warburg effect, cell proliferation, invasion and migration by downregulating PFKFB2 expression in lung cancer

Shikonin inhibits the Warburg effect, cell proliferation, invasion and migration by downregulating PFKFB2 expression in lung cancer

Shikonin Inhibits Cancer Through P21 Upregulation and Apoptosis Induction

Uncovering of the Association Between m5C Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characteristics in Hepatocellular Carcinoma

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